Progress Reports

Reporting Period:

Year 1

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During this award period we have researched and constructed a multi-modal imaging platform allowing for non-destructive analysis of vascular tissues scaffolds/constructs and have begun the validation of this platform in two study models. Our current platform integrates unique optical imaging and spectroscopy technologies with advanced ultrasound techniques. The optical component is designed to provide a rapid assessment of vascular constructs biochemical features with high molecular sensitivity as well as to imaging the construct microstructure with very high resolution. The ultrasound component is designed to image rapidly the construct morphology as well as to measure the construct mechanical properties or local elastic properties that subsequently can be correlated with construct functionality. Moreover, we have developed a 3D printed system for production and cellular repopulation of vessels. Additionally, we have developed two model systems for assessment of cellular interaction with their supporting tissue environment – the extracellular matrix niche. These model systems have been utilized to assess the effect of the extracellular matrix niche on behavior of human stem cells. Importantly, we have demonstrated that different extracellular matrix niches are capable of modulating stem cell growth and function. We have further demonstrated that the bimodal non-invasive imaging platform developed under this proposal has high sensitivity for assessing small differences in extracellular matrix niche. The developed bimodal system therefore has potential for monitoring presence of seeded cells and the effect such cells on turnover of their extracellular matrix environment.

Reporting Period:

Year 4 NCE

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<p>This CIRM award has enabled the construction of a multimodal imaging platform for simultaneous fluorescence lifetime imaging and ultrasound or optical coherence tomography. The instrument is fiberoptic-based and can be used to study biochemical, structural and functional features in the inner wall of vascular constructs in situ and non-destructively. The imaging platform has been coupled to a home-built bioreactor that allows for continuous optical monitoring of scaffold recellularization and extracellular matrix remodeling under distinct flow conditions. </p><p>We have validated the ability of the imaging platform to resolve endothelial cells and mesenchymal stem cells as they migrate on bovine pericardium, a highly collagenous scaffold, and to resolve different compositions of the extracellular matrix (collagen and elastin) on different tissue types. The work first performed in vitro in 2D was later translated to 3D thanks to the completion of the bioreactor that allows to perform studies under physiologically relevant conditions. The next step, which this CIRM award has allowed us to evaluate, is the translation of the imaging platform to in vivo applications that permits the evaluation of graft development in large animals (e.g. swine).</p><p>In summary, the CIRM award has enabled the development of an multimodal imaging technology that allows for continuous monitoring of tissue remodeling and regeneration processes and for future testing treatments in situ, in test dishes, in bioreactors with distinct environmental conditions, and in vivo in large animal models (e.g. implanted scaffolds). The nondestructive nature of this imaging platform will enable continuous monitoring of tissue development with instant feedback, which will optimize clinical outcomes and will contribute to the development of more cost-effective tissue engineering strategies.</p>

Grant Application Details

Current vascular replacement materials are far from ideal, with all available biomaterials exhibiting significant clinical complications. The development of novel biocompatible decellularized vascular grafts holds great promise for functional restoration of vascular tissues suffering from trauma or disease. However, the need for destructive analysis at multiple in-vitro and in-vivo time points creates a costly critical bottleneck in development of such vascular biomaterials and regenerative medicine approaches. We propose to research, test and validate a tissue diagnostic technology combining optical and ultrasound imaging techniques. This platform will enable label-free, real-time, non-destructive analysis of composition, structure, function and site specific cellular repopulation of extracellular matrix of engineered vascular tissue constructs. This technology is expected to alleviate the need for destructive assays across multiple time points, which are costly and frequently impractical. The technology will facilitate (a) in-vitro rapid screening of vascular scaffold production methods; and (b) in-vivo assessment across multiple time points of vascular constructs. This technology can improve our ability to produce functional engineered vascular tissues in the laboratory for in-vivo implantation which can accelerate the integration time of the vascular implant with the surrounding host tissue, thus to contribute to restoring the desired quality of life to the patient.

Statement of Benefit to California:

Cardiovascular disease is the leading cause of death in western societies (about 1 in 5 deaths); which in combination with the prevalence of peripheral artery disease in aging population (12-20% in individuals >60 years of age) and ischemic stroke due to atherosclerosis of carotid artery make this disease the most prominent health problem in California and in the United States. New therapeutic and diagnostic technologies including advancements in vascular tissue engineering and materials for blood vessel replacement are needed. The proposed multimodal technology has the potential to improve our ability to produce functional engineered vascular tissues in the laboratory and thus to significantly impact treatment for coronary and peripheral artery disease, and to provide solutions for California’s citizens greatest health problem. In addition, the global market for vascular grafts and patches is expected to significantly increase over the next 5 years in both United States and Europe due to the prevalence of cardiovascular disease and increased number of interventional vascular procedures. Since both the imaging technology and vascular materials proposed to be evaluated in this CIRM application have potential for commercialization, advancement of this technology has the potential to contribute to California’s economic growth. Moreover, a tool for non-destructive label-free engineered tissue analysis as proposed here can accelerate research in all areas of interest to CIRM.